MARCELO LUIZ BALANCIN
Projetos de Pesquisa
Unidades Organizacionais
36 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 36
- The expression patterns and prognostic significance of pleckstrin homology-like domain family A (PHLDA) in lung cancer and malignant mesothelioma(2021) BALDAVIRA, Camila M.; MACHADO-RUGOLO, Juliana; PRIETO, Tabatha G.; BASTOS, Daniel R.; BALANCIN, Marcelo; AB'SABER, Alexandre M.; YAEGASHI, Lygia B.; SOUZA, Paola C.; FARHAT, Cecilia; TAKAGAKI, Teresa Y.; NAGAI, Maria Ap; CAPELOZZI, Vera L.Background: Pleckstrin homology domain family A (PHLDA) genes play important roles in cancer cellular processes, including inhibiting Akt activation, repressing growth factor signaling, inhibiting the negative feedback of EGFR/ErbB2 signaling cells, and inducing apoptosis. However, the prognostic significance of PHLDA in non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MM) remains unclear. The present study investigates the associations between PHLDA expression patterns and their prognostic value in lung adenocarcinoma (LUAD) and MM. Methods: We analyzed PHLDA family members at the genomic level in silico to explore their mRNA expression pattern and predictive significance in LUAD and MM. We then created a PHLDA-drug interaction network and a protein-protein interaction (PPI) network using different databases. Finally, we immunohistochemically assessed the protein expression of each PHLDA family member on tissue microarrays (TMAs) in both LUAD and MM cohorts with long-term follow-up. Results: While PHLDA1 mRNA expression in both LUAD and MM was lower than that of normal tissue, PHLDA2 mRNA was significantly overexpressed in LUAD, and PHLDA3 mRNA was overexpressed in MM. In NSCLC, both low PHLDA1 mRNA expression and high PHLDA3 mRNA expression correlated with worse overall survival (OS) (P<0.01), whereas high PHLDA2 mRNA expression was associated with better OS (P<0.01). In MM, patients presenting high PHLDA1 and PHLDA2 mRNA expression had poor OS (P=0.01 and P<0.01, respectively). In addition, the PHLDA-drug interaction network indicated that several common drugs could potentially modulate PHLDA expression, and the PPI network suggested that PHLDA1 interacts with Notch family members, whereas PHLDA3 interacts with TP53. Our results also showed that the expression of PHLDA2 and PHLDA3 was significantly higher in LUAD and MM than that of PHLDA1 (P<0.05) and was associated with the risk of death. While patients with PHLDA2 >85.09 cells/mm(2) had a low risk of death (P=0.01) and a median survival time of 48 months, those with PHLDA3 <70.38 cells/mm(2) had a high risk of death (P=0.03) and a median survival time of 34 months. Conclusions: We shed light on the role of the PHLDA family as promising predictive biomarkers and potential therapeutic targets in LUAD and MM.
- Pulmonary Neuroendocrine Neoplasms Overexpressing Epithelial-Mesenchymal Transition Mechanical Barriers Genes Lack Immune-Suppressive Response and Present an Increased Risk of Metastasis(2021) PRIETO, Tabatha Gutierrez; BALDAVIRA, Camila Machado; MACHADO-RUGOLO, Juliana; FARHAT, Cecilia; OLIVIERI, Eloisa Helena Ribeiro; SA, Vanessa Karen de; SILVA, Eduardo Caetano Abilio da; BALANCIN, Marcelo Luiz; SABER, Alexandre Muxfeldt Ab; TAKAGAKI, Teresa Yae; LIMA, Vladmir Claudio Cordeiro de; CAPELOZZI, Vera LuizaTypical carcinoids (TC), atypical carcinoids (AC), large cell neuroendocrine carcinomas (LCNEC), and small cell lung carcinomas (SCLC) encompass a bimodal spectrum of metastatic tumors with morphological, histological and histogenesis differences, The hierarchical structure reveals high cohesiveness between neoplastic cells by mechanical desmosomes barrier assembly in carcinoid tumors and LCNEC, while SCLC does not present an organoid arrangement in morphology, the neoplastic cells are less cohesive. However, the molecular mechanisms that lead to PNENs metastasis remain largely unknown and require further study. In this work, epithelial to mesenchymal transition (EMT) transcription factors were evaluated using a set of twenty-four patients with surgically resected PNENs, including carcinomas. Twelve EMT transcription factors (BMP1, BMP7, CALD1, CDH1, COL3A1, COL5A2, EGFR, ERBB3, PLEK2, SNAI2, STEAP1, and TCF4) proved to be highly expressed among carcinomas and downregulated in carcinoid tumors, whereas upregulation of BMP1, CDH2, KRT14 and downregulation of CAV2, DSC2, IL1RN occurred in both histological subtypes. These EMT transcription factors identified were involved in proliferative signals, epithelium desmosomes assembly, and cell motility sequential steps that support PNENs invasion and metastasis in localized surgically resected primary tumor. We used a two-stage design where we first examined the candidate EMT transcription factors using a whole-genome screen, and subsequently, confirmed EMT-like changes by transmission electron microscopy and then, the EMT-related genes that were differentially expressed among PNENs subtypes were predicted through a Metascape analysis by in silico approach. A high expression of these EMT transcription factors was significantly associated with lymph node and distant metastasis. The sequential steps for invasion and metastasis were completed by an inverse association between functional barrier created by PD-L1 immunosuppressive molecule and EMT transcriptional factors. Our study implicates upregulation of EMT transcription factors to high proliferation rates, mechanical molecular barriers disassembly and increased cancer cell motility, as a critical molecular event leading to metastasis risk in PNENs thus emerging as a promising tool to select and customize therapy.
- Mutational Profiling of Driver Tumor Suppressor and Oncogenic Genes in Brazilian Malignant Pleural Mesotheliomas(2020) CAMPANELLA, Nathalia C.; SILVA, Eduardo Caetano; DIX, Gustavo; VAZQUEZ, Fabiana de Lima; PAULA, Flavia Escremim de; BERARDINELLI, Gustavo N.; BALANCIN, Marcelo; CHAMMAS, Roger; V, Rossana Mendoza Lopez; SILVEIRA, Henrique Cesar S.; CAPELOZZI, Vera Luiza; REIS, Rui ManuelBackground:Malignant pleural mesothelioma (MPM) is a highly lethal disease comprising a heterogeneous group of tumors with challenging to predict biological behavior. The diagnosis is complex, and the histologic classification includes 2 major subtypes of MPM: epithelioid (similar to 60% of cases) and sarcomatous (similar to 20%). Its identification depends upon pathological investigation supported by clinical and radiological evidence and more recently ancillary molecular testing. Treatment options are currently limited, with no known targeted therapies available.Objectives:To elucidate the mutation profile of driver tumor suppressor and oncogenic genes in a cohort of Brazilian patients.Methods:We sequenced 16 driver genes in a series of 43 Brazilian malignant mesothelioma (MM) patients from 3 distinct Brazilian centers. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor tissue blocks, and theTERTpromoter region was amplified by PCR followed by direct capillary sequencing. The Illumina TruSight Tumor 15 was used to evaluate 250 amplicons from 15 genes associated with solid tumors (AKT1, GNA11, NRAS, BRAF, GNAQ, PDGFRA, EGFR, KIT, PIK3CA, ERBB2, KRAS, RET, FOXL2, MET,andTP53). Library preparation with the TruSight Tumor 15 was performed before sequencing at the MiSeq platform. Data analysis was performed using Sophia DDM software.Results:Out of 43 MPM patients, 38 (88.4%) were epithelioid subtype and 5 (11.6%) were sarcomatoid histotype. Asbestos exposure was present in 15 (39.5%) patients with epithelioid MPM and 3 (60%) patients with sarcomatoid MPM. We founda TERTpromoter mutation in 11.6% of MM, and the c.-146C>T mutation was the most common event. The next-generation sequencing was successful in 33 cases. A total of 18 samples showed at least 1 pathogenic, with a median of 1.8 variants, ranging from 1 to 6. The most mutated genes wereTP53andERBB2with 7 variants each, followed byNRASBRAF,PI3KCA,EGFRandPDGFRAwith 2 variants each.KIT,AKT1, andFOXL2genes exhibited 1 variant each. Interestingly, 2 variants observed in thePDGFRAgene are classic imatinib-sensitive therapy.Conclusions:We concluded that Brazilian MPM harbor mutation in classic tumor suppressor and oncogenic genes, which might help in the guidance of personalized treatment of MPM.
- Mesothelin expression remodeled the immune-matrix tumor microenvironment predicting the risk of death in patients with malignant pleural mesothelioma(2023) QUALIOTTO, Aline Nery; BALDAVIRA, Camila Machado; BALANCIN, Marcelo; AB'SABER, Alexandre; TAKAGAKI, Teresa; CAPELOZZI, Vera LuizaBackgroundThe combination of immunobiological agents with immune checkpoint proteins is a promising treatment for malignant pleural mesothelioma (MPM). Mesothelin and anti-PD-L1 antibody-drug conjugates specifically target malignant neoplastic cells, inhibit the migration and invasion of neoplastic cells, and restore the immune landscape. In this study, we confirmed the importance of mesothelin and examined the relationship between mesothelin and the immune landscape of the tumor microenvironment (TME) in two MPM cohorts.MethodsThe discovery cohort included 82 MPM cases. Tissue microarray slides were generated, and samples were processed for hematoxylin & eosin staining, immunohistochemistry, and immunofluorescence assays. The relationship between mesothelin, biomarkers of histogenesis, histological aggressiveness, PD-L1, immune cells (CD4, CD8, CD20, CD68), and collagen type I and type V fibers was evaluated by quantitative digital analyses. The outcome was the survival time until death from disease recurrence. The exploratory cohort included 87 malignant mesothelioma (MESO) patients from The Cancer Genome Atlas database.ResultsMost patients were male (70.7%) with a history of asbestos exposure (53.7%) and with the epithelioid subtype (89%). Surgical resection was performed in 85.4% of patients, and 14.6% received chemotherapy; 59.8% of patients died from disease extension to the mediastinum. Low tumor mesothelin expression was associated with tumor necrosis and nuclear grade 1, whereas high mesothelin expression was significantly associated with the epithelioid histotype and high density of T cells CD8+, macrophages CD68+, and collagen type I fibers. Cox multivariate analysis showed a high risk of death for non-operated patients [hazard ratio (HR), 3.42 (1.15-10.16)] with low tumor mesothelin levels [HR, 2.58 (1.09-6.10)] and high PD-L1 and low infiltration of T cells CD4+ [HR, 3.81 (1.58-9.18)]. In the exploratory cohort, low mesothelin and high COL1A1 and COL5A1 expression were associated with poor overall survival.ConclusionTumor mesothelin expression associated with the TME immune landscape predicts the risk of death for patients with MPM and could be a new target for immunotherapy in MPM.
conferenceObject Pleckstrin Homology-Like (PHLDA) Domain Family Members Immunoexpression as Prognostic Marker in Lung Cancer and Mesothelioma(2021) BALDAVIRA, C. Machado; PRIETO, T.; BALANCIN, M.; EHER, E.; FERNEZLIAN, S.; SOUZA, P.; NAGAI, M.; CAPELOZZI, V.- Comprehensive analysis of immune, extracellular matrices and pathogens profile in lung granulomatosis of unexplained etiology(2018) SOUZA, Paola da Costa; DONDO, Patricia Suemi; SOUZA, Gabriela; LOPES, Deborah; MOSCARDI, Marcel; MARTINHO, Vinicius de Miranda; LOURENCO, Rodolfo Daniel de Mattos; PRIETO, Tabatha; BALANCIN, Marcelo Luiz; ASSATO, Aline Kawassaki; TEODORO, Walcy Rosolia; RODRIGUES, Silvia; LIMA, Mariana; CASTELLANO, Maria Vera; COLETTA, Ester; PARRA, Edwin Roger; CAPELOZZI, Vera LuizaThis study analyzed the type 1 and type 2 T helper (Th1/Th2) cytokines (including interleukins), immune cellular, matrix profile, and pathogens in granulomas with unexplained etiology compared to those with infectious and noninfectious etiology. Surgical lung biopsies from 108 patients were retrospectively reviewed. Histochemistry, immunohistochemistry, immunofluorescence, morphometry and polymerase chain reaction were used, respectively, to evaluate total collagen and elastin fibers, collagen I and III, immune cells, cytokines, matrix metalloproteinase-9, myofibroblasts, and multiple usual and unusual pathogens. No relevant polymerase chain reaction expression was found in unexplained granulomas. A significant difference was found between the absolute number of eosinophils, macrophages, and lymphocytes within granulomas compared to uninvolved lung tissue. Granulomas with unexplained etiology (UEG) presented increased number of eosinophils and high expression of interleukins (ILs) IL-4/IL-5 and transforming growth factor-beta. In sarcoidosis, CD4/CD8 cell number was significantly higher within and outside granulomas, respectively; the opposite was detected in hypersensitivity pneumonitis. Again, a significant difference was found between the high number of myofibroblasts and matrix metalloproteinase-9 in UEG, hypersensitivity pneumonitis, and sarcoidosis compared to granulomas of tuberculosis. Granulomas of paracoccidioisis exhibited increased type I collagen and elastic fibers. Th1 immune cellular profile was similar among granulomas with unexplained, infectious, and noninfectious etiology. In contrast, modulation of Th2 and matrix remodeling was associated with more fibroelastogenesis and scarring of lung tissue in UEG compared to infectious and noninfectious. We concluded that IL-4/IL-5 and transforming growth factor-beta might be used as surrogate markers of early fibrosis, reducing the need for genotyping, and promise therapeutic target in unexplained granulomas.
conferenceObject A dynamic macrophagic environment in xanthogranulomatous mastitis: a broader clue to xanthomatous diseases pathophysiology and clinical evolution?(2020) CLEMENTE, L. Campos; MARQUES-PIUBELLI, M.; BALANCIN, M.; REIS, L.; CAPELOZZI, V. L.conferenceObject Paratesticular fibrous pseudotumour and the importance of immunohistochemical evaluation of IgG4/IgG ratio(2018) MEDEIROS, G.; MORGANTETTI, G.; BALANCIN, M.; CAPELOZZI, V.- Combining Immunoprofile, Immunogenic Collagen and Mismatch Repair Proteins Predicts Risk of Death and Target Therapy in Malignant Mesothelioma(2019) MACHADO-RUGOLO, J.; BALANCIN, M.; MARTINS, V.; MIRANDA, J.; ASSATO, A.; SOUZA, N.; VELOSA, A. P.; FALZONI, R.; AB'SABER, A.; TEODORO, W.; CAPELOZZI, V.
conferenceObject Immune-profilling depends on immunogenic collagen and mismatch proteins to predict death and therapy in malignant mesothelioma(2019) MORGANTETTI, G.; BALANCIN, M.; MARTINS, V.; MIRANDA, J. T. De; ASSATO, A. K.; SOUZA, N. A. de; VELOSA, A. P. Pereira; TEODORO, W. Rosolia; MEDEIROS, G. A. de; FALZONI, R.; AB'SABER, A. M.; CAPELOZZI, V.